Average Follow-up Time Detail"Median follow- up time was 6.0 years for controls and 6.1 years for cases."As there were an equal number of cases and controls, the averaged (rounded) follow-up time for the entire cohort is 6.1.

Exposure DetailNondrinkers:0 drinks/week (nondrinker for many years; not a recent quitter or former drinker); Former (quit drinking within 5 years prior to baseline; and Quitter (quit drinking over the course of the study)Drinkers:less than 1 drink/week, 1 to 6 drinks/week, 7 to 13 drinks/week, 14 or more drinks/week.All amounts were averages of all annual self-reported intakes weekly.

"At yearly visits, participants were individually asked the usual number of 12-oz cans or bottles of beer, 6-oz glasses of wine, and shots of liquor that they drank at a time and the usual frequency with which they consumed those beverages. In primary analyses, we averaged alcohol consumption from the baseline questionnaire and the questionnaire from the annual clinic visit closest to the date of the MRI examination. In secondary analyses, we used alcohol consumption determined from these 2 assessments individually.

At baseline, participants reported whether they changed their pattern of consumption during the past 5 years and whether they ever regularly consumed 5 or more drinks daily. Participants who reported abstention at baseline but responded yes to either of these questions were classified as former drinkers. Participants who reported some alcohol consumption at baseline but abstention at the time of MRI were classified as quitters separate from former drinkers.

As in previous CHS analyses,7 we categorized participants according to weekly alcohol consumption for primary analyses as follows: none, former, quitter, less than 1 drink, 1 to 6 drinks, 7 to 13 drinks, and 14 or more drinks weekly. For logistic regression analyses, we used abstainers without former use as the reference category, to minimize the inclusion of sick quitters.42 We performed additional analyses that incorporated alcohol consumption (in drinks per week) as a continuous variable, performing log transformation because of the skewed distribution of alcohol consumption in CHS. When these analyses included nondrinkers, we added 0.01 drinks per week to all observations to allow log transformation."

Ethnicity DetailThere were 81 (11%) black participants and the remainder are presumed to be Caucasian.

Age DetailParticipants were an average of 77.7 (77.5 cases + 77.8 controls/ 2) years of age at the time of analysis, but as this was a nested case-control, the average age at the start of follow-up is not presented.

Screening and Diagnosis DetailScreening Method:

3MSE

Modified Mini-Mental State Examination (Teng 1987)

AD Diagnosis:

DSM IV

Diagnostic and Statistical Manual IV

IQ-CODE

Informant Questionnaire for Cognitive Decline in the Elderly (Jorm 1989)

Total dementia definition: Dementia determined using the CHS Cognition Study four stage protocol.

"Of the 3660 participants who completed an MRI, 3608 completed a 3MSE at the same clinical visit and were eligible for the CHS cognition study (FIGURE). We determined their subsequent risk of dementia using the CHS Cognition Study protocol.31,32 Investigators performed a multistage screening process on all eligible participants, whether or not they were still alive, beginning in 1999. When a participant died before that time, determination of dementia was made using available medical records, previous CHS testing, and Informant Questionnaire on the Cognitive Decline of the Elderly (IQCODE) questionnaires33 sent to each participant’s personal physician and proxy respondent. Investigators obtained similar information from participants who were alive but did not complete the full screening process.

The first stage of the screening process identified participants at particular risk of dementia for intensive subsequent evaluation. Low-risk participants were alive in 1999 and had no history of stroke or dementia, 3MSE scores of 80 or above throughout 1997- 1999, and no decline in 3MSE score from 1992-1994 to 1999 greater than 5 points, consistent with previous studies of cognitive decline in CHS.34 At 3 of the 4 CHS sites (n=2681), high-risk participants and all black participants (because of their smaller sample size and higher underlying risk35) then underwent further evaluation in a second stage; low-risk participants (n=1492) were considered not to have dementia. At the Pittsburgh site, all participants (n=927), irrespective of risk status, were further evaluated in a second stage.

In the second stage, participants underwent a full neuropsychiatric battery. At the Pittsburgh site, all available participants underwent further neurological testing in a third stage; at the other 3 sites, participants with abnormal tests of memory or of any 2 other domains underwent further evaluation.

In the third stage, neurologists performed detailed neurological examinations, reviewed previously collected information, and classified participants as having no cognitive impairment, mild cognitive impairment, or dementia.31 Neurologists completed the Unified Parkinson’s Disease Rating Scale,36 and the Hachinski Ischemic Scale.37 They diagnosed dementia based on a progressive or static cognitive deficit of sufficient severity to affect a participant’s activities of daily living, and history of normal intellectual function before the onset of cognitive abnormalities. Participants were required to have impairments in 2 cognitive domains, which did not necessarily include memory.

In the fourth stage, a neurologist with extensive experience in dementia reviewed all subjects diagnosed by local neurologists as free of dementia to ensure that no cases were missed. An adjudication committee of study neurologists or psychiatrists from the 4 CHS clinics then reviewed cases classified as possible dementia in the third and fourth stages, confirmed the diagnoses, and established types of dementia. The classification of dementia type was done after review of the 1992-1994 MRI results although the diagnosis of dementia per se was not affected by the results of the MRI. The adjudication committee based its classifications on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,38 National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer Disease and Related Disorders Association,39 State of California Alzheimer’s Disease Diagnostic and Treatment Centers,40 and National Institute of Neurological Diseases and Stroke-Association Internationale pour la Recherche et 1l’Enseignement en Neurosciences.41

Finally, to ensure that all participants with incident dementia were free of dementia at the start of follow-up, we excluded subjects who died within 2 years of undergoing an MRI, had a 3MSE score of less than 80 at the time of their MRI, or had no follow-up testing performed after undergoing an MRI. Based on results from the Pittsburgh site, in which all participants (rather than just high-risk participants) underwent full evaluation, our overall estimates of dementia are approximately 9% lower than if we had fully evaluated all participants.31"

Covariates & Analysis DetailAnalysis Type:Logistic regression

"We used a nested case-control approach to assess the relative odds of incident dementia according to alcohol consumption. We frequency-matched all participants with incident dementia to an equal number of participants without dementia on the basis of age (in 5-year increments), death before the end of follow-up in 1999, and completion of a CHS clinic visit in 1998-1999. We used logistic regression to control for potentially confounding factors and included the matching variables in all models.47"

AD Covariates:

A

age

G

gender

APOE4

APOE e4 genotype

DM

diabetes mellitus

RE

race/ethnicity

SH

stroke history

§ Covariates for total dementia are different.

TD Covariates:

A

age

E

education

G

gender

APOE4

APOE e4 genotype

AF

atrial fibrillation

BMI

body mass index

CHF

congestive heart failure history

DM

diabetes mellitus

ERT

estrogen replacement therapy

MS

marital status

PA

physical activity

RE

race/ethnicity

SM

smoking status

SES

socioeconomic status

SH

stroke history

TC

total cholesterol

TIA

transient ischemic attack history

Cases (based on TD) and controls "frequency-matched on age, death before 1999, and their attendance of a 1998-1999 clinic."

AD covariates include "age, sex, race, diabetes, APOE e4, and history of stroke." Note: the analysis of AD was not adjusted for education.

In sex-stratified analyses, results differed slightly for men and women. Women displayed a generally inverse relationship, with lower odds among women who consumed 7 or more drinks per week. In contrast, men had a U-shaped relationship between alcohol use and odds of both AD and dementia.

In analyses of total dementia stratified by APOE e4 status, results were stronger in persons who were e4 negative. Higher levels of alcohol status appeared to increase the odds of dementia in persons who had the e4 allele, although the precision of those estimates were limited due to small sample size.